Program Project Grant

Treatment of Malignant Brain Tumors

Brain tumors affect more than 17,000 people in the United States each year, and cause more than 13,000 deaths. Although brain tumors are a prominent cause of cancer death in young adults and children, they are most common among middle-aged and older adults, and the incidence in people older than 65 years of age is increasing. Glioblastoma multiforme (GM) and anaplastic astrocytoma (AA)-the most malignant brain tumors with the poorest prognosis-comprise a significant proportion of these tumors.

The overall goal of this program is to integrate advances in technological development of physiologic neuro-imaging and tissue biomarkers in the management of patients with brain tumors and to translate this knowledge to optimize delivery of novel agents into the brain parenchyma.

Project Summaries

Project 1: Improved Management of
Glioblastoma by Integrated
Imaging and Tissue AnalysisPrincipal Investigator: Sarah Nelson PhD
Project Summary: The previous cycle of the BTRC Program Project Grant
was focused on determining
which noninvasive metabolic
and physiological imaging
parameters are valuable
for characterizing newly
diagnosed and post-treatment
glioblastoma (GBM) and to
link these metrics with ex
vivo metabolic profiles and
histological characteristics.
Diffusion-weighted imaging,
perfusion imaging, and MR
spectroscopy parameters can
provide useful information on
tumor burden and response to
treatment.

Over the next cycle of the
Program Project Grant (2013-2017),
investigators will validate
the metrics defined in the
previous funding cycle and
applying them to routine
clinical practice. These metrics
include the myoinositol/
choline index derived from
MR spectroscopy, which
was shown to be a relevant
biomarker for gliosis. More
than 250 patients with newly
diagnosed and post-treated
glioblastoma have been
enrolled in image-guided
biopsy studies to correlate
histologic, genomic, and
metabolic characteristics with
physiological imaging features.

Project 2: Image-guided Genomics to Understand
Tumor Heterogeneity and Evolution
Principal Investigators: Susan Chang MD and Joseph Costello PhD
Project Summary: The goal of this investigation
is to evaluate newly
diagnosed and posttreated
glioblastoma with
specific emphasis on the
genomic features of tumor
heterogeneity and evolution.
Changes in the tumor from
time of initial diagnosis to
progression occur at the
molecular level – both as part
of the natural history of the disease and as an effect of
therapies. Determining the
genetic changes at the time
of progression and correlating
them to physiologic and
metabolic imaging could
more accurately reflect
the biological behavior of
recurrent glioblastoma.
The information gleaned
from these studies will
be especially useful for evaluating agents that
target specific dysregulated
pathways within a given
tumor. If the activated
pathways change from
initial diagnosis to recurrence,
patients will need to be
enrolled in new protocols
that are appropriate for the
new molecular signature of
their tumor.

Project 3: Hyperpolarized 13C MRSI Monitoring of
Pyruvate Metabolism to Assess Drug Action
Principal Investigators: Russell Pieper PhD and Sabrina Ronen PhDProject Summary: The final group of
experiments in the BTRC
Program Project Grant
explores ex vivo, in vivo,
and clinical development of
hyperpolarized 13C imaging
as a biomarker of drug
delivery and response to
therapy. UCSF is one of the
only institutions with this
technology and this study
will represent the first-ever
application of hyperpolarized
13C imaging to patients with
brain tumors.

Preliminary studies in
glioblastoma models
indicate that response to therapeutic agents such
as temozolomide, PI3K/
mTOR inhibitors, and histone
deacetylase inhibitors is
associated with a drop in the
activity of enzymes involved
in pyruvate metabolism,
including pyruvate kinase and
lactate dehydrogenase. This
manifests in a tumor-specific
decrease in the conversion of
hyperpolarized 13C pyruvate
to 13C lactate and a drop in
the ratio of hyperpolarized
lactate to pyruvate (Lac/Pyr)
detectable by 13C MRS and
MRSI within the first week
of treatment. Hyperpolarized 13C Lac/Pyr may therefore
serve as a novel biomarker
of response to therapy and
could allow clinicians to
rapidly assess early response
to treatment and make critical
decisions regarding changes
in drug therapy faster.
Clinical evaluation of
hyperpolarized 13C imaging
will be performed in
conjunction with the first
project funded by the
Program Project Grant,
which is vetting new imaging
parameters in clinical studies.

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